The present invention relates to a novel process for the preparation of racemates consisting of 6-thiatetracycline derivates of "natural" configuration and their optical antipodes.
Hereinafter, the term "6-thiatetracycline" is used to refer to a racemate which consists of 4-dimethylamino-1,4,4a,5,5a,6-11,12a-octahydro-3,10,12,12a-tetrahydroxy-1, 11-dioxo-6-thia-naphthacene-2-carboxamide having the configuration indicated in the formula. ##STR1## and its optical antipode.
A configuration in which the C.sub.(4) amino group and the two hydrogen atoms on C.sub.(4a) and C.sub.(5a) are in the syn-position relative to one another (as in 6-thiatetracycline) is termed "natural" herein, since it encompasses that of the naturally occurring tetracyclines produced by micro-organisms.
6-Thiatetracycline derivatives are known, for example from German Offenlegungsschrift No. 2,437,487 (U.S. Pat. No. 3,988,468) and German Offenlegungsschrift No. 2,442,829 (U.S. Pat. No. 4,024,272). In the syntheses described in these specifications, the tetracyclic system (octahydro-6-thianaphthacene) can be formed by a condensation reaction of 2-phenyl-4-[2-(5-hydroxy-thiochroman-4-on-2-yl)-ethylidene]-2-thiazolin-5- one (or oxazolin-5-one) with acetonedicarboxylic acid monomethyl ester monoamide. A mixture of the 4 possible racemates of 1,4,4a,5,5a,6,11,12a-octahydro-3,12-dihydroxy-1,11-dioxo-6-thianaphthacene -2-carboxamides, I to IV, is thus obtained which are shown schematically below: ##STR2##
IV corresponds to the "natural" configuration. Compounds having this configuration display the greatest antibacterial activity and are therefore preferred. Efforts will therefore be made to convert the isomers I, II, and III, which belong to the less active series, into the isomer IV, the "4.alpha., 4a.alpha., 5a.alpha."-antipode of which belongs to the most active series.
Thus, it is possible (see the above referenced U.S. patents) to epimerize the substituent in the 4-position in the desired manner, for example, by permitting it to stand in pyridine or piperidine. In this way, I can be converted into II and III can be converted into IV. Thus, using the crude product from the described condensation reaction as the starting material, a mixture can be obtained which consists only of II and IV.
These prior art processes, for example, epimerize by treating the stereoisomeric derivative with piperidine at 20.degree. C. for 31/2 hours (U.S. Pat. No. 3,988,468, column 7, lines 45-48) or with pyridine at 20.degree. C. for 3 days (U.S. Pat. No. 4,024,272, column 11, lines 48-50).
However, hitherto, no route was known for converting the less desired II into the valuable IV. Therefore, in general, the resulting mixture had to be separated into its two components. This is a troublesome procedure because of the chemical similarity of the two components. For example, it was achievable using chromatographic methods. Moreover, in general, the isomer II had to be discarded since it could not be converted into secondary products which were pharmacologically active in vivo.